Since the 1980s, statins have been the mainstream therapy of low-density lipoprotein cholesterol (LDL-C) reduction and the prevention of atherosclerotic cardiovascular disease (ASCVD). However, many patients fail to achieve optimal cholesterol levels during treatment. In recent years, innovative therapies based on oligonucleotides and gene editing have emerged, offering broader patient benefits, longer-lasting effects, and even the potential for a one-time, permanent reduction in cholesterol levels.

Lowering LDL-C Levels: The Key to Preventing ASCVD Risk

With continuous societal development and improving living standards, modern lifestyles have introduced significant health challenges. Increased work pressure, sedentary habits, and poor dietary choices have become major triggers for cardiovascular diseases. The rising incidence of atherosclerosis caused by hyperlipidemia has become a critical threat to human health. As a result, maintaining cardiovascular health and exploring new therapeutic targets to further reduce residual cardiovascular risk have become key research directions in the field of lipid-lowering therapies.

Lipid Metabolism Pathway ¹

Atherosclerosis caused by hyperlipidemia is classified as a metabolic disease. Under normal conditions, when endothelial cells remain intact, lipids are efficiently transported and metabolized via lipoprotein particles. However, when vascular endothelium is damaged, cholesterol-rich low-density lipoprotein (LDL) particles can accumulate in the vessel walls, leading to atherosclerosis. As macrophages engulf LDL, local inflammation and oxidative stress intensify, further promoting the formation of atherosclerotic plaques and worsening vascular health.

Common lipid profile markers include total cholesterol, triglycerides, LDL-C, and high-density lipoprotein cholesterol (HDL-C). However, lipid composition is more complex, involving components such as lipoprotein (a) (Lp(a)), free fatty acids, and phospholipids. These lipids bind to apolipoproteins to form different lipoprotein particles, allowing them to remain soluble in the bloodstream and be transported throughout the body to support cellular metabolism. The size and density of lipoproteins are crucial to their function, with LDL serving as the primary carrier of cholesterol, accounting for approximately 70% of total blood cholesterol. Consequently, lowering LDL-C levels has become a core strategy in reducing the risk of ASCVD.

Longer-Lasting and Broader Coverage: Innovative Therapies Leading the New Direction in Lipid-Lowering

While statin therapies have demonstrated significant efficacy in lowering LDL-C and preventing cardiovascular diseases; however, they have limitations. Firstly, statin effectiveness varies among individuals, and some patients fail to achieve optimal cholesterol levels. Secondly, side effects such as muscle symptoms, liver function abnormalities, and an increased risk of diabetes may impact patient adherence. Additionally, statins have limited effects on other lipid components and cannot fully eliminate all cardiovascular risks, while genetic factors may also influence treatment outcomes. Compared to traditional statins, innovative therapies such as oligonucleotides and gene editing offer greater precision, long-term efficacy, and patient adherence, particularly for statin-intolerant or non-responsive patients.

• 「PCSK9, ANGPTL3」RNA Interference (RNAi) Therapies: Strong Adherence and Broad Benefits

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) promotes the degradation of LDL receptors (LDL-R), leading to the accumulation of LDL-C in the bloodstream and increasing the risk of atherosclerosis. Novartis' RNAi therapy, Leqvio (Inclisiran), binds to the mRNA that encodes the PCSK9 protein, using RNA interference to reduce its levels. This prevents the liver from producing PCSK9, thereby promoting LDL-R recycling and effectively clearing LDL-C. The drug has been approved by the FDA for the treatment of adult patients with primary hyperlipidemia, including those with heterozygous familial hypercholesterolemia (HeFH). Compared to other PCSK9 inhibitors, Leqvio requires only two injections per year and works synergistically with statins for better outcomes. In 2023, Leqvio (Inclisiran) received FDA approval for an expanded indication to treat patients with elevated LDL-C and increased cardiovascular risk. In August 2024, Novartis announced that Leqvio successfully reduced LDL-C levels in patients with medium and low-risk ASCVD in the Phase 3 V-MONO clinical trial, strongly supporting its broader application as a cardiovascular disease prevention therapy.²

On the other hand, Arrowhead Pharmaceuticals' targeted angiopoietin-like 3 (ANGPTL3) RNAi therapy, Zodasiran, has entered Phase 3 clinical trials. Results from the Phase 2 trial, published in May 2024, showed that the highest dose of Zodasiran reduced triglyceride levels by 63% and residual cholesterol levels by 82% after 24 weeks.³

• Several Pharmaceutical Companies Advancing 「Lp(a)」 Antisense Oligonucleotide Lipid-Lowering Therapy Development

Lp(a) is an independent genetic risk factor for cardiovascular diseases, affecting approximately 20% of the global population. Its levels are determined by genetics and cannot be controlled through lifestyle changes. Currently, no effective therapy specifically targets lowering Lp(a) levels, despite attempts to regulate it with drugs like niacin, which have had limited success. Research shows that PCSK9 monoclonal antibodies can effectively lower Lp(a) while reducing LDL-C, providing significant cardiovascular protection for patients with high baseline Lp(a) levels. Currently, several Lp(a)-targeted antisense oligonucleotide lipid-lowering therapies are currently in clinical development, including Novartis' Pelacarsen, Amgen's Olpasiran, Ionis' Zerlasiran, and Eli Lilly's Lepodisiran. These trials aim to assess the effectiveness and safety of reducing Lp(a) levels.4 In particular, Amgen's Olpasiran in the OCEAN-DOSE trial showed that even after one year of discontinuation, patients' Lp(a) levels remained at low levels, with more than 98% of patients reducing their Lp(a) levels to the standard value of 125 nmol/L or lower. Additionally, Eli Lilly's RNAi therapy, Lepodisiran, has entered Phase 3 clinical trials, with early data showing that a single treatment can sustain a near one-year reduction in Lp(a) levels, demonstrating the durability of its efficacy.⁵

• 「PCSK9, ANGPTL」Base Editing Therapies Offer Potential for One-Time Lipid-Lowering Treatment

Building on the foundation of oligonucleotide therapies that reduce treatment frequency, base editing therapies provide a more longer, even permanent, treatment solution. Verve Therapeutics has developed VERVE-102, a base editing therapy that targets the PCSK9 gene for permanent inactivation, effectively lowering LDL-C levels in the blood. This therapy utilizes Verve's proprietary GalNAc-modified lipid nanoparticle (LNP) delivery technology, ensuring more specific liver targeting and better tolerability. VERVE-102 is currently undergoing Phase 1b clinical trials, and BioPharma Dive has listed it as one of the top ten clinical trials to watch in 2025.6 Additionally, another base editing therapy from Verve Therapeutics, VERVE-201, is also in Phase 1b clinical trials. This therapy uses the company's developed GalNAc-LNP nanoparticle delivery platform to deliver a base editor targeting the ANGPTL3 gene, a key regulator of cholesterol and triglyceride levels in the liver. The goal is to permanently disrupt the production of ANGPTL3 protein, thereby lowering LDL-C and residual cholesterol levels. Compared to the PCSK9-targeted base editing therapy, the ANGPTL3-targeted editing therapy offers the advantage of using lipid nanoparticles with GalNAc ligands, which can bind to the asialoglycoprotein receptor (ASGPR) in the liver. This allows patients with homozygous familial hypercholesterolemia (HoFH), who lack LDL-R, to also benefit from the therapy by facilitating drug uptake into the liver, thus expanding the patient population.⁷

High-Quality Tools for Lipid Metabolism Research and Drug Development

ACROBiosystems provides a comprehensive suite of tools to support the development of oligonucleotide, gene-editing, and antibody-based therapies targeting lipid metabolism. Our offerings include:

• PCSK9 recombinant proteins，ANGPTL3 recombinant proteins: Both are expressed in human-derived cells HEK293 and validated by SDS-PAGE, SEC-MALS, ELISA, SPR, featuring high purity, high activity, high batch-to-batch consistency. They are suitable for applications in immunization, antibody screening, and candidate drug functional validation.

• PCSK9 [Biotinylated]: LDL R Inhibitor Screening ELISA Assay Pair: Utilizing unique biotinylated proteins to develop high-quality inhibitor screening reagents, paired with applicable methodologies for inhibitor screening and QC release.

• A variety of high-quality targeted drug development tools for lipid-lowering drug development for hyperlipidemia, including ASGR1，THRA，THRB，LDL-R，APOA-II，APOE，APOH，LPL are also available, fully supporting your drug development research!

All products undergo rigorous batch-to-batch quality control, with verified purity and binding activity. Free protocols are available to streamline your drug development.

References：

1. Lina Badimon, Gemma Chiva-Blanch, Chapter 24 - Lipid Metabolism in Dyslipidemia and Familial Hypercholesterolemia, Editor(s): Vinood B. Patel, The Molecular Nutrition of Fats, Academic Press, 2019, Pages 307-322, ISBN 9780128112977, https://doi.org/10.1016/B978-0-12-811297-7.00024-X.

2. https://www.novartis.com/research-development/novartis-pipeline?search_api_fulltext=Leqvio

3. https://arrowheadpharma.com/pipeline/

4. https://www.amgen.com/newsroom/press-releases/2023/08/amgen-presents-late-breaking-phase-2-olpasiran-data-at-esc-2023

5. https://jamanetwork.com/journals/jama/fullarticle/2811935

6. https://www.vervetx.com/our-programs/verve-101-102

7. https://www.vervetx.com/our-programs/verve-201